The bisphosponic acids and their pharmaceutically acceptable salts are an important class of medicaments that act as specific inhibitors of Osteoclast-mediated bone resorption and are useful in the treatment of bone disorders such as Paget's disease and osteoporosis. Bisphosphonates are synthetic analogs of pyrophosphate that bind to the hydroxy-appetite found in the bone.
Bisphosphonates such as 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid (Risedronate) have been proposed for use in the treatment of diseases of bone and calcium metabolism. Such diseases include osteoporosis, hyperparathyroidism, hypercalcemia of malignancy, ostolytic bone metastases, myosistis ossifcans progressiva, calcinoisis universalis, arthritis, neuritis, bursitis, tendonitis and other inflammatory conditions. At present Paget's disease and heterotropic ossification are successfully treated with both ethane-1-hydroxy-1,1-diphosphonic acid (EHDP) and Risedronate.
The bisphosphonates tend to inhibit the resorption of bone tissue, which is beneficial to patients suffering from excessive bone loss. However, in spite of certain analogies in biological activity, all bisphosphonates do not exhibit the same degree of biological activity. The salt and hydrate forms of bisphosphonates alter both their solubility and their bioavailability.
Bisphosphonates are capable of existing in several polymorphic or pseudopolymorphic forms. The polymorphs and pseudopolymorphs can be influenced by controlling the conditions under which the salt is obtained in solid form, for example by controlling conditions of crystallization. Solid-state physical properties that can differ from one polymorph (or pseudopolymorph) to the other include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch, or tribasic calcium phosphate.
The above mentioned bisphosphonates were disclosed in U.S. Pat. No. 5,583,122, describing some of the bisphosphonate compounds like Risedronic acid and their pharmaceutical compositions comprising the said compounds.
It is known in the literature that Risedronate sodium exists in three hydration states: monohydrate, hemi-pentahydrate and anhydrous form. U.S. Pat. No. 6,410,520 describes selective crystallization of Risedronate sodium as a monohydrate or hemi-pentahydrate. The ratio of hemi-pentahydrate to monohydrate crystal forms in the product can be effectively controlled by varying the water to 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid sodium ratio and isopropanol to water ratio as well as the temperature.
Further, U.S. '520 patent discloses, that the monohydrate and the hemi-pentahydrate are preferred forms and that the hemi-pentahydrate is the thermodynamically preferred crystalline form under processing conditions based on the observation that the monohydrate crystals convert to the hemi-pentahydrate form.
It is therefore desirable to provide an efficient process to selectively produce Risedronate sodium hemi-pentahydrate with high purity and high yield.
We have now found that, in the process of the present invention Risedronic acid is first treated with organic amine base to give Risedronate amine group followed by replacement of amine group with sodium ion producing Risedronate sodium in pure hemi-pentahydrate form in high yield and high purity.